Technical Field
The present invention relates to pharmaceutical compounds. More particularly, the present invention relates to gold(III) complexes having mixed diamine ligands. The present invention includes the use of these gold(III) complexes for treatment of cancers and cell proliferative disorders.
Description of the Related Art
The “background” description provided herein is for the purpose of generally presenting the context of the disclosure. Work of the presently named inventors, to the extent it is described in this background section, as well as aspects of the description which may not otherwise qualify as prior art at the time of filing, are neither expressly or impliedly admitted as prior art against the present invention.
The development of new metal based therapeutic drugs with a pharmacological activity different from platinum drugs is one of the major goals of modern bioinorganic and bio-organometallic medicinal chemistry research [Bertrand B, Bodio E, Richard P, Picquet M, Gendre P L, Casini A (2015) J. Organomet. Chem. 775:124-129; Sadler P J, Sue R E (1994) Met. Based Drugs 1:107-144; Sava G, Bergamo A, Dyson P J (2011) Dalton Trans. 40:9069-9075; Shaw C F (1999) Chem. Rev. 99:2589-2600; Best S L and Sadler P J (1996) Gold Bull. 29:87-93; vanRijt S H and Sadler P J (2009) Drug Discov. Today 14(23-24):1089-1097; Panteli N, Stanojkovi T P, Zmejkovski B B, Sabo T J, Kaluderovic G N (2015) European Journal of Medicinal Chemistry 90:766-774; Al-Jaroudi S S, Fettouhi M, Wazeer M I M, Isab A A, Altuwaijri S (2013) Polyhedron 50:434-442—each incorporated herein by reference in their entirety]. The high effectiveness of cisplatin in the treatment of several types of tumors is severely hindered by some clinical problems such as normal tissue toxicity and the frequent occurrence of initial and acquired resistance to the drug [Kelland L (2007) Nat. Rev. Cancer 7:573-584; Thayer A M (2010) Eng. News 88:24-28; Dhar S, Lippard S J (2011) Bioinorg. MedChem, Wiley-VCH, Ch 3:79-96; Wang X, Guo X Z (2011) Bioinorganic MediChem, Wiley-VCH, Ch 4:97-149—each incorporated herein by reference in its entirety]. Gold(III) complexes, which are isoelectronic and isostructural to platinum(II) complexes, show promising antitumor activity [Sadler P J (1976) Struct. Bond 29:171-214; Cutillas N, Yellol G S, de Haro C, Vicente C, Rodriguez V, Ruiz J (2013) Coord. Chem. Rev. 257:2784-2797—each incorporated herein by reference in their entirety]. Gold(III) complexes have recently gained considerable attention because they have strong antiproliferative effects and exhibited pharmacodynamics and kinetic properties that are different from cisplatin [Shaw C F (1999) Chem. Rev. 99:2589-2600—incorporated herein by reference in its entirety]. In general, gold(III) complexes are unstable under physiological conditions because they have a high reduction potential and hydrolyze fast. Therefore, selecting suitable ligands to enhance the stability of gold(III) complexes is a challenge.
In view of the foregoing, the present disclosure aims to provide stable gold(III) complexes having efficacy against a variety of cancers that also lack the severe toxic side effects associated with platinum-based drugs.
Brief Summary of the Invention
According to a first aspect, the present disclosure relates to a gold(III) complex having Formula I:
or a pharmaceutically acceptable salt, solvate, or prodrug thereof. The group, W, is selected from W1 or W2.
R1-R8 are each independently a hydrogen, an optionally substituted C1-C8 alkyl group, or an optionally substituted C6-C8 aryl group. R9-R14 are each independently a hydrogen, a halogen, a hydroxyl, an amino, a nitro, a cyano, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted arylalkyl, an optionally substituted heteroaryl, an optionally substituted alkoxyl, an optionally substituted thioalkoxyl, an optionally substituted aryl, a N-monosubstituted amino group, or a N,N-disubstituted amino group. R15-R26 are each independently a lone pair of electrons, a hydrogen, a halogen, a hydroxyl, an amino, a nitro, a cyano, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted arylalkyl, an optionally substituted heteroaryl, an optionally substituted alkoxyl, an optionally substituted thioalkoxyl, an optionally substituted aryl, a N-monosubstituted amino group, or a N,N-disubstituted amino group. Z1-Z4 are each independently a carbon, an oxygen, a sulfur, or a nitrogen atom. Z5-Z8 are each independently a carbon, or a nitrogen atom.
In some embodiments, the gold(III) complex has a formula selected from the group consisting of Formula II, Formula III, and Formula IV:

In at least one embodiment, the gold(III) complex is a pharmaceutically acceptable salt having one or more pharmaceutically acceptable anions selected from the group consisting of fluoride, chloride, bromide, iodide, nitrate, sulfate, phosphate, methanesulfonate, ethanesulfonate, p-toluenesulfonate, salicylate, malate, maleate, succinate, tartrate, citrate, acetate, perchlorate, trifluoromethanesulfonate, acetylacetonate, hexafluorophosphate, and hexafluoroacetylacetonate.
According to a second aspect, the present disclosure relates to a composition comprising the gold(III) complex or a pharmaceutically acceptable salt, solvate or prodrug thereof, and one or more pharmaceutically acceptable carriers.
In some embodiments, the composition further comprises one or more other active pharmaceutical agents.
In at least one embodiment, the composition has 50-99.9 wt% of the gold (III) complex relative to the total weight of the composition.
In some embodiments, the composition is in solid, semi-solid or liquid dosage forms.
In most embodiments, the composition is formulated for one or more modes of administration, including, oral administration, systemic administration, parenteral administration, inhalation spray, infusion, rectal administration, topical administration, intravesical administration, intradermal administration, transdermal administration, subcutaneous administration, intramuscular administration, intralesional administration, intracranial administration, intrapulmonal administration, intracardial administration, intrasternal administration, and sublingual administration.
According to a third aspect, the present disclosure relates to a method for treating one or more types of cancer in a mammalian subject in need thereof, by administering a therapeutically effective amount of the composition of the second aspect to the mammalian subject.
In at least one embodiment, the gold(III) complex or a pharmaceutically acceptable salt, solvate or prodrug thereof, is administered in a dose of 0.05 mg/kg to 200 mg/kg based on the weight of the mammalian subject.
In some embodiments, the one or more types of cancer are prostate cancer and/or gastrointestinal cancer.
In at least one embodiment, the one or more types of cancer is resistant to cisplatin.
In at least one embodiment, the mammalian subject has renal disease.
According to a fourth aspect, the present disclosure relates to a method for inhibiting proliferation of cancer cells by contacting the cancer cells with the gold(III) complex or a pharmaceutically acceptable salt, solvate or prodrug thereof.
In some embodiments, the cancer cells are human cells.
In at least one embodiment, the cancer cells are prostate cancer cells and/or gastrointestinal cancer cells.
In some embodiments, the prostate cancer cells are PC3 cells, and the gastrointestinal cancer cells are SGC7901 cells.
In some embodiments, the gold(III) complex exhibits an IC50 of 1-20 μM for inhibiting the proliferation of the cancer cells.
The foregoing paragraphs have been provided by way of general introduction, and are not intended to limit the scope of the following claims. The described embodiments, together with further advantages, will be best understood by reference to the following detailed description taken in conjunction with the accompanying drawings.